Project Summary Only 15-30% of individuals that experiment with drugs of abuse transition to addiction, suggesting that individual differences prior to drug experience contribute to addiction vulnerability. Such individual variability has been modelled in rodents and in humans using phenotypic behavioral differences termed sign- and goal- tracking. Sign-trackers show enhanced cue sensitivity prior to drug experience that predicts greater cue-driven drug-seeking and increased cue-induced relapse to drug-seeking compared to goal-trackers. Cue-evoked dopamine in the Nucleus Accumbens (NAc) is a neurobiological feature of sign-, but not goal-tracking. Dopamine (DA) release in the NAc plays a critical, sign-tracking specific, role in influencing the attracting properties of a reward-predictive cue. Sign-trackers are also more sensitive to the reinforcing properties of cues showing greater conditioned reinforcement effects, which are also influenced by NAc DA manipulations. This project examines an important, yet understudied regulator of the dopamine system; endocannabinoids, which bind the cannabinoid receptor 1 (CB1). The Ventral Tegmental Area (VTA) provides dense dopaminergic projections to the NAc and VTA DA neurons are regulated by endocannabinoids to influence DA release in the NAc. I hypothesize that CB1 receptor signaling in the VTA regulates NAc DA levels to control the attracting and reinforcing properties of the reward-predictive cue in sign-tracking rats. First, I will combine intra-VTA CB1 receptor blockade with Fast-Scan Cyclic Voltammetry to measure DA release in the NAc during Pavlovian lever autoshaping and conditioned reinforcement tasks. Second, I will test the necessity of the VTANAc DA projection for sign-tracking and conditioned reinforcement and the sufficiency for this projection to reverse the motivational deficits caused by intra-VTA CB1 receptor blockade. Through these experiments, I aim to elucidate novel molecular and circuit-based mechanisms that contribute to addiction susceptibility.